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A super-enhancer regulated RNA-binding protein cascade drives pancreatic cancer

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy in need of new therapeutic options. Using an unbiased analysis of super-enhancers (SEs) as sentinels of core genes involved in cell-specific function, we uncover a druggable SE-mediated RNA-binding protein (RBP) cascade that supports PDAC growth through enhanced mRNA translation. This cascade is driven by a SE associated with the RBP heterogeneous nuclear ribonucleoprotein F, which stabilizes protein arginine methyltransferase 1 (PRMT1) to, in turn, control the translational mediator ubiquitin-associated protein 2-like. All three of these genes and the regulatory SE are essential for PDAC growth and coordinately regulated by the Myc oncogene. In line with this, modulation of the RBP network by PRMT1 inhibition reveals a unique vulnerability in Myc-high PDAC patient organoids and markedly reduces tumor growth in vivo. Our study highlights a functional link between epigenetic regulation and mRNA translation and identifies components that comprise unexpected therapeutic targets for PDAC.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

DISEASE(S): Pancreatic Cancer

SUBMITTER: Jolene Diedrich

LAB HEAD: Ronald M. Evans

PROVIDER: PXD030423 | Pride | 2023-06-15

REPOSITORIES: Pride

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			Action	DRS
	20190202_RECA-1-3-DM_bRP-1.mzXML	Mzxml
	20190202_RECA-1-3-DM_bRP-1.raw	Raw
	20190202_RECA-1-3-DM_bRP-2.mzXML	Mzxml
	20190202_RECA-1-3-DM_bRP-2.raw	Raw
	20190202_RECA-1-3-DM_bRP-3.mzXML	Mzxml

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A super-enhancer regulated RNA-binding protein cascade drives pancreatic cancer

Project description:We uncovered a super-enhancer (SE)-mediated pathway, integrated by Myc, that regulates protein translation to drive pancreatic tumor growth. A SE associated with heterogeneous nuclear ribonucleoprotein F (HNRNPF) controls its expression to regulate protein arginine methyltransferase 1 (PRMT1) mRNA stability. In turn, PRMT1 asymmetrically dimethylates ubiquitin-associated protein 2-like (UBAP2L) to mediate protein translation and thus tumor growth. Deletion of any of these 3 genes, or of the super-enhancer itself, all lead to a drastic reduction in tumor burden in orthotopic PDAC models. Inhibition of PRMT1 induces apoptosis and significantly reduces tumor growth. This unexpected role of HNRNPF, PRMT1 and UBAP2L in regulating tumorigenesis by coordinating protein translation underpins this pathway, downstream of Myc, as a potential therapeutic target for PDAC.

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